Age-related macular degeneration (AMD) is the leading cause of acquired blindness in the United States. Patients with early disease suffer from limited and ineffective options for prevention and treatment. To address this shortcoming, this proposal focuses on the mechanisms underlying early disease. Evidence suggests that aging of the retinal pigmented epithelium (RPE) and Bruch membrane is the result of accumulated genetic and environmental influences. These changes help to set the stage for the development of AMD. Among the many cellular and biochemical changes associated with the transition from "normal" aging to AMD, critical factors include i) apoptosis of the RPE, ii) accumulation of apolipoprotein B100 lipoproteins and basal deposits in Bruch membrane, and iii) complement-mediated inflammation. A more thorough understanding of the biology and relationship between these processes will not only provide insights into the mechanisms of early AMD, but also targets for therapeutic intervention. Our previous funding period focused on how advanced glycation endproducts (AGEP), cross-links formed by a series of nonenzymatic glycation reactions in the matrix, altered the RPE-Bruch membrane phenotype. Information from these investigations has helped us formulate the following inter-related hypotheses: i) aging-related lipid accumulation in the RPE stimulates lipoprotein secretion, and if excessive, apoptosis, ii) aging-related changes (i.e. AGEP cross-links) to Bruch membrane promote lipoprotein retention and modification, and iii) modified lipoproteins induce complement activation which in turn, contributes to apoptosis and basal deposits. Our overall strategy is to take advantage of the synergy that results from a multidisciplinary approach that will use in vitro experiments, genetically modified mice, and human histopathologic correlation to address our hypotheses with the following specific aims: 1.) Determine whether fatty acid accumulation stimulates lipoprotein secretion by the RPE, and if the secretion pathway is overloaded, whether fatty acid accumulation leads to RPE apoptosis. 2.) Determine i) the origin of lipoproteins in Bruch membrane, and ii) whether advanced glycation endproduct (AGEP)-related changes to Bruch membrane promote lipoprotein retention. 3.) Determine whether retained lipoproteins induce complement mediated inflammation and whether this is linked to RPE apoptosis and basal deposit formation.